It is well known that progression through the cell cycle is governed by a series of checkpoint controls, otherwise referred to as restriction points, which are regulated by a family of enzymes known as the cyclin-dependent kinases (cdks). In turn, the cdks themselves are regulated at many levels such as, for instance, binding to cyclins.
The coordinated activation and inactivation of different cyclin/cdk complexes is necessary for normal progression through the cell cycle. Both the critical G1-S and G2-M transitions are controlled by the activation of different cyclin/cdk activities. In G1, both cyclin D/cdk4 and cyclin E/cdk2 are thought to mediate the onset of S-phase. Progression through S-phase requires the activity of cyclin A/cdk2 whereas the activation of cyclin A/cdc2 (cdk1) and cyclin B/cdc2 are required for the onset of mitosis. For a general reference to cyclins and cyclin-dependent kinases see, for instance, Kevin R. Webster et al, in Exp. Opin. Invest. Drugs, l998, Vol. 7(6), 865-887.
Checkpoint controls are defective in tumor cells due, in part, to disregulation of cdk activity. For example, altered expression of cyclin E and cdks has been observed in tumor cells, and deletion of the cdk inhibitor p27 KIP gene in mice has been shown to result in a higher incidence of cancer.
Increasing evidence supports the idea that the cdks are rate-limiting enzymes in cell cycle progression and, as such, represent molecular targets for therapeutic intervention. In particular, the direct inhibition of cdk/cyclin kinase activity should be helpful in restricting the unregulated proliferation of a tumor cell.
WO2007090794 (Nerviano Medical Sciences) discloses therapeutic combinations between a cdk inhibitor and monoclonal antibodies or antimitotic agents such epothilone or taxanes like docetaxel or paclitaxel. WO2004110455, WO2004041308 and WO2003077999 (Cyclacel Ltd.) relate to the combinations of a cdk inhibitor and CPT-11, gemcitabine or 5-fluorouracil respectively. WO2005094830 (Pfizer, Inc.) describes combinations of signal transduction inhibitors such as cdks inhibitors and WO2003020272 (Bristol-Myers Squibb Co.) describes combination of protein kinase inhibitors with therapeutic agents.
There is a continuous need of combination of known anticancer drugs in order to optimise the therapeutic treatment.
Some pyrazoloquinazolines have been demonstrated to be potent inhibitors of cyclin dependent kinase enzymes, particularly Cdk2. One of these compounds is currently in development as an anti-cancer agent. Cdks inhibitors are understood to block passage of cells from the G2/M phase of the cell cycle.
The present invention provides new combinations of a Cdks inhibitor with known pharmaceutical agents that are particularly suitable for the treatment of proliferative disorders, especially cancer. More specifically, the combinations of the present invention are very useful in therapy as antitumor agents and lack, in terms of both toxicity and side effects, the drawbacks associated with currently available antitumor drugs.